Title: Combination of ciclopirox olamine and sphingosine-1-phosphate as granulation enhancer in diabetic wounds
Authors : Lim, Natalie Sheng Jie
Sham, Adeline
Chee, Stella Min Ling
Chan, Casey
Raghunath, Michael
Published in : Wound repair and regeneration
Volume(Issue) : 24
Issue : 5
Pages : 795
Pages to: 809
Publisher / Ed. Institution : Wiley
Issue Date: 2016
License (according to publishing contract) : Licence according to publishing contract
Type of review: Peer review (Publication)
Language : English
Subject (DDC) : 571: Physiology and related subjects
617: Surgery
Abstract: Granulation tissue formation requires a robust angiogenic response. As granulation tissue develops, collagen fibers are deposited and compacted. Forces generated in the wake of this process drive wound contraction to reduce the wound area. In diabetics, both angiogenesis and wound contraction are diminished leading to impaired wound healing. To emulate this pathology and to address it pharmacologically, we developed a wound healing model in the diabetic Zucker fatty rat and tested a topical proangiogenic strategy combining antifungal agent ciclopirox olamine (CPX) and lysophospholipid sphingosine‐1‐phosphate (S1P) to promote diabetic wound closure. In vitro, we demonstrated that CPX + S1P up‐regulates a crucial driver of angiogenesis, hypoxia‐inducible factor‐1, in endothelial cells. Injection of CPX + S1P into subcutaneously implanted sponges in experimental rats showed, in an additive manner, a fivefold increased endothelial infiltration and lectin‐perfused vessel length. We developed a splinted diabetic rodent model to achieve low wound contraction rates that are characteristic for the healing mode of diabetic ulcers in humans. We discovered specific dorsal sites that allowed for incremental full‐thickness excisional wound depths from 1 mm (superficial) to 3 mm (deep). This enabled us to bring down wound contraction from 51% in superficial wounds to 8% in deep wounds. While the effects of topical gel treatment of CPX + S1P were masked by the rodent‐characteristic dominant contraction in superficial wounds, they became clearly evident in deep diabetic wounds. Here, a fivefold increase of functional large vessels resulted in accelerated granulation tissue formulation, accompanied by a 40% increase of compacted thick collagen fibers. This was associated with substantially reduced matrix metalloproteinase‐3 and ‐13 expression. These findings translated into a fivefold increase in granulation‐driven contraction, promoting diabetic wound closure. With CPX and S1P analogues already in clinical use, their combination presents itself as an attractive proangiogenic treatment to be repurposed for diabetic wound healing.
Departement: Life Sciences and Facility Management
Organisational Unit: Institute of Chemistry and Biotechnology (ICBT)
Publication type: Article in scientific Journal
DOI : 10.1111/wrr.12463
ISSN: 1524-475X
URI: https://digitalcollection.zhaw.ch/handle/11475/12186
Appears in Collections:Publikationen Life Sciences und Facility Management

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